Biorenewable Resources in the Biginelli Reaction: Cerium(III)-Catalyzed Synthesis of Novel Iminosugar-Annulated Perhydropyrimidines

Abstract

An unprecedented version of the Biginelli reaction using an unprotected aldose as a biorenewable aldehyde component and 2-phenyl-1,3-oxazol-5-one as a novel active methylene building block with urea/thiourea is reported. The reaction is cerium(III)-­catalyzed, expeditious, and effected under solvent-free microwave irradiation conditions to yield diastereoselectively, iminosugar-annulated polyfuntionalized perhydropyrimidines via ring transformation of an isolable intermediate followed by cyclodehydration.

Biginelli reaction - iminosugars - perhydropyrimidines - microwaves - stereoselective - solvent-free

References and Notes

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26

General Procedure for Iminosugar-Annulated Perhydropyrimidines 4 and 5: A solvent-free mixture of oxazolone 1 (2.0 mmol), aldose 2 (2.0 mmol), urea/thiourea 3 (2.0 mmol) and Ce₂(SO₄)₃ (0.114 g, 10 mol%) was taken in a 20-mL vial and subjected to MW irradiation for 8-13 min (Table [1] ). After completion of the reaction as indicated by TLC, H₂O (10 mL) was added to the reaction mixture and stirred for 10 min. The yellowish precipitate thus obtained was washed with H₂O to give the crude product which was recrystallized from EtOH to afford a diastereomeric mixture (>94:<6; in the crude products the ratio was >91:<9, as determined by ¹H NMR spectroscopy). The product on second recrystallization from EtOH furnished an analytically pure sample of a single diastereomer 4 or 5 (Table [1] ). On the basis of comparison of J values with the literature ones, [24] [30-36] the trans stereochemistry was assigned to 4 and 5, as the coupling constant (J _1,9a = 9.6 Hz) of the major trans isomer was higher than that for the minor cis diastereomer (J _1,9a = 4.8 Hz).
Characterization Data of Representative Compounds: Compound 4a: pale yellow powder; mp 115-117 °C. IR (KBr): 3341, 3315, 3009, 1685, 1670, 1675, 1603, 1581, 1455 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆ + D₂O): δ = 2.65 (dd, J _6ax,eq = 13.1 Hz, J _6ax,7 = 9.7 Hz, 1 H, H-6_ax), 3.34 (ddd, J _7,8 = 9.3 Hz, J _6ax,7 = 9.7 Hz, J _6eq,7 = 3.7 Hz, 1 H, H-7), 3.70 (dd, J _7,8 = 9.3 Hz, J _8,9 = 9.2 Hz, 1 H, H-8), 3.92 (dd, J _6ax,eq = 13.1 Hz, J _6eq,7 = 3.7 Hz, 1 H, H-6_eq), 4.11 (dd, J _8,9 = 9.2 Hz, J _9,9a = 9.5 Hz, 1 H, H-9), 5.05 (dd, J _1,9a = 9.6 Hz, J _9,9a = 9.5 Hz, 1 H, H-9a), 6.17 (d, J _1,9a = 9.6 Hz, 1 H, H-1), 7.19-7.83 (m, 5 H, ArH). ¹³C NMR (DMSO-d ₆/TMS): δ = 25.5, 59.7, 69.5, 73.5, 74.5, 80.5, 126.9, 127.7, 129.2, 130.8, 132.5, 165.7, 167.8, 169.3. MS (FAB): m/z = 336 [MH⁺]. Anal. Calcd for C₁₅H₁₇N₃O₆: C, 53.73; H, 5.11; N, 12.53. Found: C, 53.47; H, 5.33; N, 12.89.
Compound 5a: pale yellow powder; mp 125-128 °C. IR (KBr): 3343, 3319, 3008, 1683, 1667, 1673, 1604, 1585, 1449 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆ + D₂O): δ = 3.13 (ddd, J _6,7 = 9.7 Hz, J _{1 ′ a,6} = 5.8 Hz, J _{1 ′ b,6} = 2.5 Hz, 1 H, H-6), 3.35 (dd, J _7,8 = 9.4 Hz, J _6,7 = 9.7 Hz, 1 H, H-7), 3.50 (dd, J _{1 ′ a,1 ′ b} = 12.2 Hz, J _{1 ′ a,6} = 5.8 Hz, 1 H, Ha-1′), 3.69 (dd, J _7,8 = 9.4 Hz, J _8,9 = 9.3 Hz, 1 H, H-8), 3.81 (dd, J _{1 ′ a,1 ′ b} = 12.2 Hz, J _{1 ′ b,6} = 2.5 Hz, 1 H, Hb-1′), 4.14 (dd, J _8,9 = 9.3 Hz, J _9,9a = 9.4 Hz, 1 H, H-9), 4.99 (dd, J _1,9a = 9.5 Hz, J _9,9a = 9.4 Hz, 1 H, H-9a), 6.21 (d, J _1,9a = 9.5 Hz, 1 H, H-1), 7.08-7.85 (m, 5 H, ArH). ¹³C NMR (DMSO-d ₆/TMS): δ = 25.9, 61.1, 66.9, 70.3, 73.5, 74.5, 79.9, 127.2, 128.3, 129.7, 131.5, 133.1, 165.2, 166.9, 169.1. MS (FAB): m/z = 366 [MH⁺]. Anal. Calcd for C₁₆H₁₉N₃O₇: C, 52.60; H, 5.24; N, 11.50. Found: C, 52.89; H, 5.59; N, 11.33.

27

General Procedure for 5-Aminoperhydropyrimidine-dione Analogues 9 and 10: Compound 4 or 5 (2.0 mmol) was refluxed in H₂SO₄-H₂O (15 mL, 4:3) for 45 min in an oil bath. The reaction mixture was cooled, the desired products 9 or 10 were precipitated by adding concd NH₄OH (specific gravity 0.88) under ice cooling and recrystallized from EtOH to obtain analytically pure samples of 9 and 10, respectively.
Characterization Data of Representative Compounds:
Compound 9a: pale yellow powder; mp 134-135 °C. IR (KBr): 3345, 3011, 1683, 1669, 1605, 1579, 1451 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆ + D₂O): δ = 2.67 (dd, J _6ax,eq = 13.1 Hz, J _6ax,7h = 9.8 Hz, 1 H, H-6_ax), 3.35 (ddd, J _7,8 = 9.3 Hz, J _6ax,7h = 9.8 Hz, J _6eq,7h = 3.8 Hz, 1 H, H-7), 3.73 (dd, J _7,8 = 9.3 Hz, J _8,9 = 9.3 Hz, 1 H, H-8), 3.95 (dd, J _6ax,eq = 13.1 Hz, J _6eq,7h = 3.8 Hz, 1 H, H-6_eq), 4.09 (dd, J _8,9 = 9.3 Hz, J _9,9a = 9.5 Hz, 1 H, H-9), 5.04 (dd, J _1,9a = 9.7 Hz, J _9,9a = 9.5 Hz, 1 H, H-9a), 6.18 (d, J _1,9a = 9.7 Hz, 1 H, H-1). ¹³C NMR (DMSO-d ₆/TMS): δ = 25.6, 60.1, 69.3, 73.7, 74.6, 80.8, 165.8, 167.9. MS (FAB): m/z = 232 [MH⁺]. Anal. Calcd for C₈H₁₃N₃O₅: C, 41.56; H, 5.67; N, 18.17. Found: C, 41.92; H, 5.49; N, 18.32.
Compound 10a: pale yellow powder; mp 151-153 °C. IR (KBr): 3344, 3009, 1685, 1671, 1601, 1583, 1453 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆ + D₂O): δ = 3.15 (ddd, J _6,7 = 9.7 Hz, J _{1 ′ a,6} = 5.9 Hz, J _{1 ′ b,6} = 2.4 Hz, 1 H, H-6), 3.36 (dd, J _7,8 = 9.4 Hz, J _6,7 = 9.7 Hz, 1 H, H-7), 3.57 (dd, J _{1 ′ a,1 ′ b} = 12.1 Hz, J _{1 ′ a,6} = 5.9 Hz, 1 H, Ha-1′), 3.71 (dd, J _7,8 = 9.4 Hz, J _8,9 = 9.2 Hz, 1 H, H-8), 3.79 (dd, J _{1 ′ a,1 ′ b} = 12.1 Hz, J _{1 ′ b,6} = 2.4 Hz, 1 H, Hb-1′), 4.11 (dd, J _8,9 = 9.2 Hz, J _9,9a = 9.5 Hz, 1 H, H-9), 5.02 (dd, J _1,9a = 9.6 Hz, J _9,9a = 9.5 Hz, 1 H, H-9a), 6.23 (d, J _1,9a = 9.6 Hz, 1 H, H-1). ¹³C NMR (DMSO-d ₆/TMS): δ = 26.0, 61.5, 67.0, 70.5, 73.6, 74.7, 80.2, 165.3, 167.2. MS (FAB): m/z = 262 [MH⁺]. Anal. Calcd for C₉H₁₅N₃O₆: C, 41.38; H, 5.79; N, 16.09. Found: C, 41.18; H, 5.58; N, 16.21.

28 Kappe CO. J. Org. Chem.  1997,  62:  7201 

29

General Procedure for Isolation of Michael Adducts 7a ( n = 3, X = O, R = H) and 7j ( n = 4, X = S, R = Ph) and Their Conversion into the Corresponding Sugar-Annulated Products 4a and 5d:
The procedure followed was the same as described above for the synthesis of 4 and 5 except that the time of MW irradiation in this case was 4-6 min instead of 8-13 min. The adducts 7 were recrystallized from EtOH to give a diastereomeric mixture (>94:<6; in the crude products the ratio was >91:<9, as determined by ¹H NMR spectroscopy) which was again recrystallized from EtOH to obtain an analytical sample of 7a and 7j. The adducts 7a and 7j were assigned the anti stereochemistry as their ¹H NMR spectra exhibited higher values of coupling constant (J _{cyclicNCH,acyclicNCH} = 9.9 Hz) than that of the very minor (<6%) diastereomer (syn, J _{cyclicNCH,acyclicNCH} = 4.4 Hz). [24] [30-36] Finely powdered intermediate compounds 7a and 7j were MW irradiated for 4-7 min in the same way as described for the synthesis of 4 and 5 to give the corresponding sugar-annulated products 4a and 5d quantitatively.
Characterization Data of Representative Compounds:
Compound 7a: pale yellow powder; mp 102-104 °C. IR (KBr): 3148, 3011, 1773, 1677, 1603, 1585, 1455 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆ + D₂O): δ = 4.07 (dd, J _{1 ′ ,2 ′} = 6.9 Hz, J _{1 ′ ,acyclicNCH} = 5.4 Hz, 1 H, H-1′), 4.19 (dd, J _{4 ′ Ha,Hb} = 10.5 Hz, J _{4 ′ Hb,3 ′} = 5.3 Hz, 1 H, H_b-4′), 4.39 (dd, J _{1 ′ ,2 ′} = 6.9 Hz, J _{2 ′ , 3 ′} = 4.1 Hz, 1 H, H-2′), 4.67 (ddd, J _{3,4 ′ Hb} = 5.3 Hz, J _{3,4 ′ Ha} = 5.3 Hz, J _{2 ′ , 3 ′} = 4.1 Hz, 1 H, H-3′), 4.85 (dd, J _{4 ′ Ha,Hb} = 10.5 Hz, J _{3,4 ′ Ha} = 5.3 Hz, 1 H, 4′-H_a), 5.03 (dd, J _{1 ′ ,acyclicNCH} = 5.4 Hz, J _{cyclicNCH,acyclicNCH} = 9.9 Hz, 1 H, acyclic NCH), 6.74 (d, J _{cyclicNCH,acyclicNCH} = 9.9 Hz, 1 H, cyclic NCH), 7.12-7.69 (m, 5 H, ArH). ¹³C NMR (DMSO-d ₆): δ = 35.8, 64.9, 70.5, 71.5, 72.7, 73.5, 73.5, 74.6, 127.5, 128.3, 130.2, 132.9, 133.6, 167.5, 170.2. MS (FAB): m/z = 354 [MH⁺]. Anal. Calcd for C₁₅H₁₉N₃O₇: C, 50.99; H, 5.42; N, 11.89. Found: C, 50.79; H, 5.78; N, 11.63.

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